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Article(id=1322934903939146396, tenantId=1146029695717560320, journalId=1319373162502258839, issueId=1322934685818564977, articleNumber=null, orderNo=null, doi=10.16016/j.2097-0927.202411028, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=null, receivedDate=1730822400000, receivedDateStr=2024-11-06, revisedDate=1732204800000, revisedDateStr=2024-11-22, acceptedDate=null, acceptedDateStr=null, onlineDate=1793341860040, onlineDateStr=2026-10-30, pubDate=1743264000000, pubDateStr=2025-03-30, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1793341860040, onlineIssueDateStr=2026-10-30, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1793341860040, creator=13701087609, updateTime=1793341860040, updator=13701087609, issue=Issue{id=1322934685818564977, tenantId=1146029695717560320, journalId=1319373162502258839, year='2025', volume='47', issue='6', pageStart='489', pageEnd='628', issueExtLink='null', onlineDate='null', pubDate='1743264000000', pubDateStr='2025-03-30', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=null, createTime=1793341808037, creator='13701087609', updateTime=1793341808037, updator='13701087609', preIssue=null, nextIssue=null, articleTotal=null, ext=null, issueFiles=null, downloadFileDto=null}, startPage=539, endPage=550, ext={EN=ArticleExt(id=1322934905600090782, articleId=1322934903939146396, tenantId=1146029695717560320, journalId=1319373162502258839, language=EN, title=AKT1-mediated autophagy of hepatocellular carcinoma cells enhances cell sensitivity to 125I seed irradiation, columnId=1320434418116837551, journalTitle=Journal of Army Medical University, columnName=Basic Medicine, runingTitle=null, highlight=null, articleAbstract=
Objective‍

To investigate the impact of serine/threonine-protein kinase 1(AKT1)-mediated autophagy in hepatocellular carcinoma (HCC) cells on their sensitivity to 125I seed irradiation.

Methods‍

① iProX database and STRING12.0 website were utilized to analyze the proteomic data of HCC before and after 125I seed irradiation to explore the differentially expressed proteins and associated functional connections. Meanwhile, The Cancer Genomics Atlas (TCGA) database was employed to analyze the relationship between AKT1 expression level and the survival of HCC patients. ② Human HCC cell lines HUH7 and Hep3B were exposed to continuous irradiation from 125I radioactive seeds with an initial apparent activity of 0.8 mCi per seed for approximately 120 h, accumulating a total dose of 8 Gy, while the control cells were cultured under normal condition for 120 h. ③ Autophagy inhibitor, chloroquine (CQ) and inducer, rapamycin (RAPA) were used to treat the HCC cells respectively to establish the CQ group and the RAPA group. The lentiviral transfection technique was employed to construct the HCC cells with overexpressed AKT1, namely the AKT1 group. The HCC cells treated in the same way were continuously irradiated with 125I seeds for 120 h to construct the CQ+125I group, the RAPA+125I group, and the AKT1+125I group. ④The changes in microtubule-associated protein light chain 3 (LC3), p62, AKT1 and p-AKT1 were detected by Western blotting. Cell immunofluorescence assay was employed to observe the expression of autophagy related proteins, such as LC3. The colony forming ability and apoptotic rate were detected with plate cloning assay and flow cytometry.

Results

① Continuous irradiation with 125I seeds resulted in decreased expression of p62 and increased ratio of LC3Ⅱ/LC3Ⅰ (P<0.05) when compared with the negative control (NC) group. Immunofluorescence assay revealed more green fluorescence spots of LC3. When compared with the 125I group, the CQ + 125I group had significantly increased expression of p62 (P<0.01), decreased ratio of LC3Ⅱ/LC3Ⅰ(P<0.01), lower apoptotic rate (P<0.01), and more colony formations (P<0.01). In contrast, the results in the RAPA + 125I group were opposite to those of the CQ + 125I group. ② Analysis on the iProX database showed that the expression of AKT1 was decreased in the irradiated group, and analysis on the TCGA database indicated that high expression of AKT1 predicted a poor prognosis for HCC patients (P<0.01). ③After irradiation with 125I seeds, the expression of AKT1 at both the RNA and protein levels was decreased in the 125I group (P<0.01). After overexpression of AKT1, the level of autophagy was decreased (P<0.05). Irradiation of HCC cells with overexpressed AKT1 using 125I seeds could partially restore the level of autophagy. In the AKT1 + 125I group, the expression of AKT1, pAKT1 and p62 were all decreased, and the ratio of LC3Ⅱ/LC3Ⅰ was increased than the AKT1 group (P<0.05). ④ The apoptotic rate of the AKT1 + 125I group was lower than that of the 125I group (P<0.05) and higher than that in the AKT1 group (P<0.05). In HUH7 cells, the clonogenic ability of the AKT1 + 125I group was higher than that of the 125I group (P<0.05). In Hep3B cells, the clonogenic ability of the AKT1 + 125I group was higher than that of the 125I group, and the clonogenic ability of the AKT1 group was higher than that of the NC group (P<0.05).

Conclusion‍

125I seed irradiation induce lethal autophagy in HCC cells by reducing the expression of AKT1, providing a new theoretical basis for the implantation of 125I radioactive seeds in the treatment of HCC.

, authors=Chenyu WANG, Zhizhou WU, li LIU, Yunhua XIAO, Xuequan HUANG, authorsList=Chenyu WANG, Zhizhou WU, li LIU, Yunhua XIAO, Xuequan HUANG, authorCompany=null, correspAuthors=Xuequan HUANG, authorNote=null, correspAuthorsNote=null, copyrightStatement=© 2025 Journal of Army Medical University, copyrightOwner=Editorial Office of Journal of Army Medical University, extLink=null, articleAbsUrl=null, sourceXml=null, magXml=null, pdfUrl=null, pdf=null, pdfFileSize=null, pdfExtLink=null, richHtmlUrl=null, mobilePdfUrl=null, reviewReport=null, pdfFirstPage=null, abstractGraph=null, abstractGraphContent=null, abstractVideo=null, citation=null, cebUrl=null, magXmlContent=null, mapNumber=null, fund=null), CN=ArticleExt(id=1322934914349408945, articleId=1322934903939146396, tenantId=1146029695717560320, journalId=1319373162502258839, language=CN, title=AKT1介导的肝癌细胞自噬增强125I粒籽辐照敏感性, columnId=1322185528879993170, journalTitle=陆军军医大学学报, columnName=基础医学, runingTitle=null, highlight=null, articleAbstract=
目的

探究丝氨酸/苏氨酸蛋白激酶1（serine/threonine-protein kinase 1，AKT1）介导的肝癌细胞自噬对125I粒籽辐照敏感性的影响。

方法

①利用iProX数据库和STRING12.0网站对125I粒籽辐照前后肝癌蛋白组数据进行分析，探究差异表达蛋白及相关功能联系，同时借助癌症基因组图谱（the cancer genome attas，TCGA）数据库分析AKT1表达水平与肝癌患者生存期关系。②利用人肝癌细胞系HUH7和Hep3B构建体外辐照模型，125I组细胞接受起始表观活度0.8 mCi/粒籽的125I放射性粒籽持续辐照约120 h累计辐射剂量8 Gy，对照组（NC组）正常培养120 h。③使用自噬抑制剂氯喹（chloroquine，CQ）、诱导剂分别处理肝癌细胞系，构建CQ组和RAPA组。运用慢病毒转染技术构建过表达AKT1肝癌细胞系，即AKT1组。将同样处理的肝癌细胞系持续125I粒籽辐照120 h，获得CQ+125I组、RAPA+125I组、AKT1+125I组。④Western blot检测微管相关蛋白轻链3（microtubule-associated protein light chain 3，LC3）、p62、AKT1、p-AKT1的变化，利用细胞免疫荧光观察LC3表达；平板克隆实验和流式细胞术实验检测细胞克隆能力以及凋亡率。

结果

①125I粒籽辐照后，相较于NC组，125I组的中p62表达降低（P<0.05），LC3Ⅱ/LC3Ⅰ比值增高（P<0.05），免疫荧光显示LC3绿色荧光点增多。与125I组比较，CQ+125I组p62表达增高（P<0.01），LC3Ⅱ/LC3Ⅰ比值降低（P<0.01）。在细胞凋亡和克隆能力方面，CQ+125I组凋亡率较125I组降低（P<0.01），CQ+125I组克隆形成数较125I组增多（P<0.01），而RAPA+125I组结果与之相反。②iProX数据库分析显示，AKT1在辐照组降低，TCGA数据库分析表明，AKT1高表达预示肝癌患者较差预后（P<0.01）。③125I粒籽辐照后，125I组AKT1在RNA和蛋白水平表达均降低（P<0.01）。过表达AKT1后，自噬水平降低（P<0.05），125I粒籽辐照过表达AKT1的肝癌细胞可部分恢复自噬水平。相较于AKT1组，AKT1+125I组的AKT1、p-AKT1、p62表达均降低（P<0.05），LC3Ⅱ/LC3Ⅰ比值增高（P<0.05）。④关于细胞凋亡和克隆能力，AKT1+125I组较125I组凋亡率降低（P<0.05），AKT1+125I组较AKT1组凋亡率升高（P<0.05）。HUH7细胞中AKT1+125I组较125I组克隆能力提高（P<0.05），在Hep3B细胞中AKT1+125I组较125I组克隆能力提高（P<0.05），AKT1组较NC组克隆能力增高（P<0.05）。

结论

125I粒籽辐照后的肝癌细胞通过降低AKT1的表达诱导致命性自噬，为125I放射性粒籽植入治疗肝癌提供了新的理论依据。

, authors=王琛禹, 吴治州, 刘丽, 肖云华, 黄学全, authorsList=王琛禹, 吴治州, 刘丽, 肖云华, 黄学全, authorCompany=null, correspAuthors=黄学全, authorNote=

作者贡献声明

王琛禹负责论文撰写、实验操作；吴治州、刘丽负责实验数据处理；肖云华负责论文修改；黄学全负责论文的设计和修改。

, correspAuthorsNote=
黄学全，E-mail：
HUANG Xuequan，E-mail：
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A：125I粒籽辐照后的肝癌细胞中差异基因进行GO富集分析；B、C：HUH7和Hep3B细胞NC组和125I组中p62与LC3Ⅰ/Ⅱ的表达 a：P<0.05，b：P<0.01，与NC组比较；D：免疫荧光检测HUH7和Hep3B细胞NC组和125I组中LC3的表达

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a：P<0.01，与NC组比较，b：P<0.01，与125I组比较A、B：HUH7和Hep3B细胞NC、125I、CQ+125I以及RAPA+125I组中p62和LC3的表达； C：流式细胞术检测HUH7和Hep3B细胞NC、125I、CQ+125I以及RAPA+125I组的凋亡率

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a：P<0.01，与NC组比较，b：P<0.01，与125I组比较

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a：P<0.001，b：P<0.01，c：P<0.05，与NC组比较A：RT-qPCR检测HUH7和Hep3B细胞中NC组和125I组中AKT1在转录水平的表达情况；B：Western blot检测HUH7和Hep3B细胞中NC组和125I组中AKT1、p-AKT1蛋白的表达

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a：P<0.05，与NC组比较；b：P<0.05，与125I组比较；c：P<0.05，与AKT1组比较A：HUH7和Hep3B细胞NC组与AKT1组中AKT1、p62和LC3的表达情况；B：HUH7和Hep3B细胞NC组、125I组、AKT1组、AKT1+125I组中AKT1、p-AKT1、p62和LC3的蛋白表达情况

, figureFileSmall=BxNjUF33QfCzYb/z+sT7hQ==, figureFileBig=nLN081I+DTk8b9LF2DfqyA==, tableContent=null), ArticleFig(id=1322934934456902380, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322934903939146396, language=EN, label=null, caption=null, figureFileSmall=wQ+BHREu0/JqcJ8BeLm1tw==, figureFileBig=v7nQj3I0B99PlX+8HmKLAg==, tableContent=null), ArticleFig(id=1322934936147206895, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322934903939146396, language=CN, label=图6, caption=过表达AKT1降低了肝癌细胞对125I粒籽辐照敏感性

a：P<0.05，与NC组比较；b：P<0.05，与125I组比较；c：P<0.05，与AKT1组比较A：流式检测NC组、125I组、AKT1组以及AKT1+125I组凋亡率；B：细胞平板克隆检测NC组、125I组、AKT1组以及AKT1+125I组的细胞克隆能力

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AKT1介导的肝癌细胞自噬增强125I粒籽辐照敏感性
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王琛禹 , 吴治州 , 刘丽 , 肖云华 , 黄学全
陆军军医大学学报 | 基础医学 2025,47(6): 539-550
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陆军军医大学学报 |基础医学 2025 , 47 (6) : 539 -550
AKT1介导的肝癌细胞自噬增强125I粒籽辐照敏感性
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王琛禹, 吴治州, 刘丽, 肖云华, 黄学全
作者信息
  • 1陆军军医大学（第三军医大学）第一附属医院核医学科，重庆
通讯作者:
黄学全，E-mail：
HUANG Xuequan，E-mail：
作者简介:

作者贡献声明

王琛禹负责论文撰写、实验操作；吴治州、刘丽负责实验数据处理；肖云华负责论文修改；黄学全负责论文的设计和修改。

AKT1-mediated autophagy of hepatocellular carcinoma cells enhances cell sensitivity to 125I seed irradiation
Chenyu WANG, Zhizhou WU, li LIU, Yunhua XIAO, Xuequan HUANG
Affiliations
  • 1Department of Nuclear Medicine，First Affiliated Hospital，Army Medical University （Third Military Medical University），Chongqing，China
出版时间: 2025-03-30 doi: 10.16016/j.2097-0927.202411028
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摘要
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目的

探究丝氨酸/苏氨酸蛋白激酶1（serine/threonine-protein kinase 1，AKT1）介导的肝癌细胞自噬对125I粒籽辐照敏感性的影响。

方法

①利用iProX数据库和STRING12.0网站对125I粒籽辐照前后肝癌蛋白组数据进行分析，探究差异表达蛋白及相关功能联系，同时借助癌症基因组图谱（the cancer genome attas，TCGA）数据库分析AKT1表达水平与肝癌患者生存期关系。②利用人肝癌细胞系HUH7和Hep3B构建体外辐照模型，125I组细胞接受起始表观活度0.8 mCi/粒籽的125I放射性粒籽持续辐照约120 h累计辐射剂量8 Gy，对照组（NC组）正常培养120 h。③使用自噬抑制剂氯喹（chloroquine，CQ）、诱导剂分别处理肝癌细胞系，构建CQ组和RAPA组。运用慢病毒转染技术构建过表达AKT1肝癌细胞系，即AKT1组。将同样处理的肝癌细胞系持续125I粒籽辐照120 h，获得CQ+125I组、RAPA+125I组、AKT1+125I组。④Western blot检测微管相关蛋白轻链3（microtubule-associated protein light chain 3，LC3）、p62、AKT1、p-AKT1的变化，利用细胞免疫荧光观察LC3表达；平板克隆实验和流式细胞术实验检测细胞克隆能力以及凋亡率。

结果

①125I粒籽辐照后，相较于NC组，125I组的中p62表达降低（P<0.05），LC3Ⅱ/LC3Ⅰ比值增高（P<0.05），免疫荧光显示LC3绿色荧光点增多。与125I组比较，CQ+125I组p62表达增高（P<0.01），LC3Ⅱ/LC3Ⅰ比值降低（P<0.01）。在细胞凋亡和克隆能力方面，CQ+125I组凋亡率较125I组降低（P<0.01），CQ+125I组克隆形成数较125I组增多（P<0.01），而RAPA+125I组结果与之相反。②iProX数据库分析显示，AKT1在辐照组降低，TCGA数据库分析表明，AKT1高表达预示肝癌患者较差预后（P<0.01）。③125I粒籽辐照后，125I组AKT1在RNA和蛋白水平表达均降低（P<0.01）。过表达AKT1后，自噬水平降低（P<0.05），125I粒籽辐照过表达AKT1的肝癌细胞可部分恢复自噬水平。相较于AKT1组，AKT1+125I组的AKT1、p-AKT1、p62表达均降低（P<0.05），LC3Ⅱ/LC3Ⅰ比值增高（P<0.05）。④关于细胞凋亡和克隆能力，AKT1+125I组较125I组凋亡率降低（P<0.05），AKT1+125I组较AKT1组凋亡率升高（P<0.05）。HUH7细胞中AKT1+125I组较125I组克隆能力提高（P<0.05），在Hep3B细胞中AKT1+125I组较125I组克隆能力提高（P<0.05），AKT1组较NC组克隆能力增高（P<0.05）。

结论

125I粒籽辐照后的肝癌细胞通过降低AKT1的表达诱导致命性自噬，为125I放射性粒籽植入治疗肝癌提供了新的理论依据。

肝癌细胞  /  125I放射性粒籽  /  AKT1  /  自噬  /  辐射敏感性
Objective‍

To investigate the impact of serine/threonine-protein kinase 1(AKT1)-mediated autophagy in hepatocellular carcinoma (HCC) cells on their sensitivity to 125I seed irradiation.

Methods‍

① iProX database and STRING12.0 website were utilized to analyze the proteomic data of HCC before and after 125I seed irradiation to explore the differentially expressed proteins and associated functional connections. Meanwhile, The Cancer Genomics Atlas (TCGA) database was employed to analyze the relationship between AKT1 expression level and the survival of HCC patients. ② Human HCC cell lines HUH7 and Hep3B were exposed to continuous irradiation from 125I radioactive seeds with an initial apparent activity of 0.8 mCi per seed for approximately 120 h, accumulating a total dose of 8 Gy, while the control cells were cultured under normal condition for 120 h. ③ Autophagy inhibitor, chloroquine (CQ) and inducer, rapamycin (RAPA) were used to treat the HCC cells respectively to establish the CQ group and the RAPA group. The lentiviral transfection technique was employed to construct the HCC cells with overexpressed AKT1, namely the AKT1 group. The HCC cells treated in the same way were continuously irradiated with 125I seeds for 120 h to construct the CQ+125I group, the RAPA+125I group, and the AKT1+125I group. ④The changes in microtubule-associated protein light chain 3 (LC3), p62, AKT1 and p-AKT1 were detected by Western blotting. Cell immunofluorescence assay was employed to observe the expression of autophagy related proteins, such as LC3. The colony forming ability and apoptotic rate were detected with plate cloning assay and flow cytometry.

Results

① Continuous irradiation with 125I seeds resulted in decreased expression of p62 and increased ratio of LC3Ⅱ/LC3Ⅰ (P<0.05) when compared with the negative control (NC) group. Immunofluorescence assay revealed more green fluorescence spots of LC3. When compared with the 125I group, the CQ + 125I group had significantly increased expression of p62 (P<0.01), decreased ratio of LC3Ⅱ/LC3Ⅰ(P<0.01), lower apoptotic rate (P<0.01), and more colony formations (P<0.01). In contrast, the results in the RAPA + 125I group were opposite to those of the CQ + 125I group. ② Analysis on the iProX database showed that the expression of AKT1 was decreased in the irradiated group, and analysis on the TCGA database indicated that high expression of AKT1 predicted a poor prognosis for HCC patients (P<0.01). ③After irradiation with 125I seeds, the expression of AKT1 at both the RNA and protein levels was decreased in the 125I group (P<0.01). After overexpression of AKT1, the level of autophagy was decreased (P<0.05). Irradiation of HCC cells with overexpressed AKT1 using 125I seeds could partially restore the level of autophagy. In the AKT1 + 125I group, the expression of AKT1, pAKT1 and p62 were all decreased, and the ratio of LC3Ⅱ/LC3Ⅰ was increased than the AKT1 group (P<0.05). ④ The apoptotic rate of the AKT1 + 125I group was lower than that of the 125I group (P<0.05) and higher than that in the AKT1 group (P<0.05). In HUH7 cells, the clonogenic ability of the AKT1 + 125I group was higher than that of the 125I group (P<0.05). In Hep3B cells, the clonogenic ability of the AKT1 + 125I group was higher than that of the 125I group, and the clonogenic ability of the AKT1 group was higher than that of the NC group (P<0.05).

Conclusion‍

125I seed irradiation induce lethal autophagy in HCC cells by reducing the expression of AKT1, providing a new theoretical basis for the implantation of 125I radioactive seeds in the treatment of HCC.

hepatocellular carcinoma cells  /  125I radioactive seeds  /  AKT1  /  autophagy  /  radiation sensitivity
王琛禹, 吴治州, 刘丽, 肖云华, 黄学全. AKT1介导的肝癌细胞自噬增强125I粒籽辐照敏感性. 陆军军医大学学报, 2025 , 47 (6) : 539 -550 . DOI: 10.16016/j.2097-0927.202411028
Chenyu WANG, Zhizhou WU, li LIU, Yunhua XIAO, Xuequan HUANG. AKT1-mediated autophagy of hepatocellular carcinoma cells enhances cell sensitivity to 125I seed irradiation[J]. Journal of Army Medical University, 2025 , 47 (6) : 539 -550 . DOI: 10.16016/j.2097-0927.202411028
正文
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原发性肝细胞癌（hepatocellular carcinoma，HCC）是全球最常见的癌症类型，在我国已成为癌症相关死亡的第二大原因［1-2］。大多数肝癌患者确诊时已处于晚期，错过了局部根治性手术或射频消融治疗的最佳时机。化疗、灌注栓塞、免疫治疗、体外放疗等常规手段虽在临床广泛应用，但疗效未达预期效果［3］。近年来，125I放射性粒籽永久植入的近距离放射治疗崭露头角，其持续低剂量率照射模式为肝癌治疗带来新契机。125I放射性粒籽持续释放29 keV γ射线，可精准破坏HCC细胞DNA，诱导癌细胞死亡。目前125I粒籽已应用于临床，并被证明是肝癌、非小细胞肺癌等恶性肿瘤的一种有效、安全、经济的治疗方法［4-6］。然而，其治疗肝癌的深层机制及治疗抵抗现象的成因仍不明晰，成为限制该技术进一步发展的关键瓶颈。丝氨酸/苏氨酸蛋白激酶1（serine/threonine-protein kinase 1，AKT1）在细胞生长过程中扮演着核心角色，不仅参与葡萄糖代谢、细胞凋亡、细胞增殖、转录和细胞迁移等环节［7］，也是肿瘤细胞转移侵袭与自噬调控的关键因子［8-9］。鉴于此，本研究聚焦125I粒籽辐照后的HCC细胞自噬现象，探究其与AKT1异常表达的相关性，旨在揭示AKT1影响肝癌细胞自噬的分子机制，为125I放射性粒籽治疗肝癌的机制阐释提供关键理论支撑，助力肝癌放疗技术的优化与突破。
1　材料与方法
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1.1　材料与试剂
HUH7和Hep3B人肝癌细胞系购自普诺赛生命科技有限公司，DMEM培养基、MEM培养基、胎牛血清和链霉素-青霉素双抗购自南京生航生物技术有限公司；125I放射性粒籽购自君安药业科技有限公司；LC3A/B抗体购自美国CST公司；p62、AKT1、p-AKT1、GAPDH和β-actin抗体均购自江苏亲科生物研究中心有限公司；抗兔IgG-HRP抗体购自美国CST公司；氯喹和雷帕霉素购自TargetMol公司。
1.2　方法
1.2.1　细胞培养和辐照处理
将HUH7细胞培养在DMEM培养基中，Hep3B细胞培养在MEM培养基中，培养基中添加10%的胎牛血清和1%的双抗，并将细胞放置在37 ℃，5%CO2的培养箱中培养。125I放射性粒籽起始表观活度为0.8 mci/粒籽，半衰期为59.4 d，发射出27.4～31.5 keV的X射线和35.5 keV的γ射线。根据先前研究所述［10］，在体外构建了辐照模型，125I组对肝癌细胞持续辐照时间约为120 h，累计总辐照剂量为8 Gy。对照组（NC组）中接种细胞于T25培养瓶中，持续培养120 h。在6孔板中，以每孔1×105个细胞的密度接种HUH7和Hep3B细胞，于各孔分别加入终浓度15 μmol/L的氯喹（chloroquine，CQ）和1 μmol/L的雷帕霉素（rapamycin，RAPA），由此构建CQ组和诱导剂RAPA组。对经同样处理的HUH7和Hep3B细胞持续辐照120 h，即为CQ+125I组和RAPA+125I组。
1.2.2　慢病毒转染细胞
构建用于过表达AKT1的慢病毒购自擎科生物有限公司。在24孔板的每个孔中接种2.5×104个肝癌细胞，培养24 h后，加入5 μL浓度为1×108 TU/mL的慢病毒转染12 h，随后更换正常培养基继续培养。在荧光显微镜下观察到有绿色荧光后，在培养基中加入2 μg/mL的嘌呤霉素培养1周，直至筛选出稳定转染的细胞后，用Western blot检测基因过表达的效率。过表达AKT1的慢病毒构建的稳定转染肝癌细胞系为AKT1组。将过表达AKT1的肝癌细胞系通过125I粒籽持续辐照120 h，即为AKT1+125I组。
1.2.3　蛋白质免疫印记实验
用RIPA裂解液提取组织和细胞中的蛋白质，并加入1%的蛋白酶抑制剂和2%的磷酸化酶抑制剂。使用BCA试剂盒检测蛋白浓度，然后加入上样缓冲液在100 ℃下变性5 min。然后使用12.5%十二烷基硫酸钠—聚丙烯酰胺凝胶电泳分离蛋白，随后转移至0.22 μm孔径PVDF膜上。在室温下封闭2 h，在4 ℃下与一抗LC3，p62，AKT1，p-AKT1，β-actin和GAPDH（1∶1 000）孵育12～14 h，在室温下与二抗（1∶4 000）孵育2 h。滴加增强发光液在膜上，反应30 s。使用化学发光成像系统记录蛋白印记，使用Image J软件分析蛋白印记灰度值。LC3A/B 合成后，羧基末端切割形成LC3A/B-Ⅰ，自噬时转变为LC3A/B-Ⅱ，在Western blot结果中，以LC3A/B-Ⅱ与LC3A/B-Ⅰ的比值（LC3Ⅱ/LC3Ⅰ）作为判断自噬水平的指标。
1.2.4　细胞免疫荧光
将细胞接种于爬片上，用4%多聚甲醛固定10 min，用0.1%Triton X-100通透15 min。使用免疫荧光快速封闭液封闭20 min，然后在4 ℃下与一抗LC3（1∶200）孵育过夜。在室温下与带有荧光标签的二抗孵育1 h。然后将爬片放置在载玻片后滴加含DAPI的抗荧光淬灭封片剂。使用激光共聚焦显微镜观察并收集图像。
1.2.5　反转录多聚酶链式反应
使用总RNA提取试剂盒进行总RNA提取，使用NanoDrop 2000系统评估RNA浓度和纯度。使用MighyScript第一链cDNA合成Master Mix对RNA样品进行反转录。使用SYBRPRIME qPCR Kit和LightCyclerTM 480系统进行qRT-PCR。采用2-△△Ct方法进行基因表达分析，使用GAPDH作为内参。
1.2.6　平板克隆实验
将细胞接种到6孔板中，起始细胞数为500个/孔，在孔板中培养24 h待细胞贴壁后再进行处理。持续培养10 d，其中实验组在细胞贴壁后开始辐照满120 h后继续培养。当集落形成后，加入4%多聚甲醛固定15 min，然后加入结晶紫染色10 min，并拍照计数存活集落的数量。
1.2.7　流式细胞术检测细胞凋亡
各实验组细胞经无EDTA胰蛋白酶消化处理，通过离心收集细胞，最终获得1～5×105个细胞的单细胞悬液。并根据Annexin-V FITC/PI凋亡检测试剂盒（4A Biotech）先加入5 μL Annexin-V FITC室温避光孵育5 min，再加入10 μL PI，并加入400 μL PBS，然后立刻上机进行流式检测。
1.2.8　数据库分析
125I粒籽辐照前后的肝癌蛋白组数据来源于iProX数据库（https://www.iprox.cn/page/home.html）。将差异表达蛋白导入STRING 12.0网站（https://cn.string-db.org/）进行蛋白质功能相关分析。癌症基因组图谱（the cancer genome attas，TCGA）数据库中肝癌总生存期和无病生存期比率的Kaplan-Meier曲线通过TCGA数据库中肝癌组织中AKT1表达水平的高低分析生成。
1.3　统计学分析
采用GraphPad Prism 9.0软件进行统计分析。所有数据均符合正态分布和方差齐性的要求，数据以x¯±s表示。组间比较采用非配对t检验，多重比较采用单因素方差分析，然后采用Tukey事后检验。P<0.05被认为差异具有统计学意义。
2　结果
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2.1　 125I粒籽辐照后的肝癌细胞产生了自噬
使用基因表达综合数据库（gene expression omnibus，GEO）与iProX蛋白组数据库中125I粒籽辐照后的肝癌细胞中差异基因进行GO富集分析，根据分析结果的气泡图可以表明，125I粒籽辐照后的肝癌细胞中的差异表达蛋白与自噬具有相关性（图1A）。随后辐照组的HUH7和Hep3B细胞在125I粒籽作用下持续辐照120 h，利用Western blot对细胞系的蛋白质进行检测，结果表明，相较于NC组，125I组中p62表达降低（P<0.05），LC3Ⅱ/LC3Ⅰ的比值增高（P<0.05，图1C）。为了进一步验证该结果，本研究对NC组和125I组的HUH7和Hep3B细胞进行了免疫荧光染色，结果表明在125I组中，LC3绿色荧光点明显增多（图1D）。综合以上结果可以表明，125I粒籽辐照后的肝癌细胞产生了自噬。
2.2　 125I粒籽诱导的致命性自噬影响肝癌细胞的辐射敏感性
本研究应用CQ和RAPA干预125I粒籽辐照后的肝癌细胞自噬表达，以探究其对放射敏感性的影响，并检测细胞存活能力与克隆能力。Western blot结果显示，相较于125I组，CQ+125I组中p62蛋白表达增高，LC3Ⅱ/LC3Ⅰ的比值降低，表明CQ可抑制125I粒籽辐照后肝癌细胞自噬；而RAPA+125I组中p62表达降低，LC3Ⅱ/LC3Ⅰ的比值增高，表明RAPA可以促进125I粒籽辐照后肝癌细胞自噬（P<0.01，图2A、B）。凋亡流式细胞术检测发现，相较于125I组，CQ+125I组凋亡率降低，RAPA+125I组凋亡率上升（P<0.01，图2C）。平板克隆实验显示，相较于125I组，CQ+125I组克隆能力升高，细胞集落形成增多；RAPA+125I组肝癌细胞的克隆能力降低（P<0.01，图2D）。以上结果表明，125I粒籽辐照后的肝癌细胞产生的自噬是一种致命性自噬，能够降低了肝癌细胞的生存能力和克隆形成能力，增加了肝癌细胞对125I粒籽放疗的敏感性。
2.3　肝癌中AKT1异常表达预示着不良预后
根据iProX数据库中125I粒籽辐照后肝癌差异蛋白表达进行分析，在辐照组和对照组中有44个差异表达蛋白。热图显示，AKT1在辐照组中表达降低（图3A）。将44个差异表达蛋白基因在STRING 12.0数据库中进行检索，随后得到差异表达基因间的相关性预测图（图3B），该结果预测了AKT1可能是125I粒籽辐照后肝癌细胞中引起蛋白变化的关键基因。根据TCGA数据库中肝细胞癌中AKT1的表达水平分析了HCC患者的总生存率和无病生存率（P < 0.01，图3C、D），结果表明，AKT1高表达预示着肝癌患者较差的预后。
2.4　 125I粒籽辐照后的肝癌细胞AKT1表达降低
2.5　过表达AKT1后125I粒籽辐照后的肝癌细胞自噬受到抑制
为了探究AKT1与125I粒籽辐照诱导自噬之间的关系，在HUH7和Hep3B细胞中过表达AKT1。利用Western blot检测肝癌细胞中AKT1的过表达效率、AKT1组以及NC组肝癌细胞的自噬水平。过表达AKT1后，相较于NC组，AKT1组的AKT1表达和p62表达均增高（P<0.05），LC3Ⅱ/LC3Ⅰ的比值降低（P<0.05，图5A），这表明过表达AKT1后自噬水平降低。下一步探究125I粒籽辐照过表达AKT1后的肝癌细胞中的自噬水平，经Western blot结果可知，相较于125I组，AKT1+125I组的AKT1、p-AKT1和p62表达均增高（P<0.05），LC3Ⅱ/LC3Ⅰ比值降低（P<0.05）；相较于较AKT1组，AKT1+125I组的AKT1、p-AKT1和p62表达均降低（P<0.05），LC3Ⅱ/LC3Ⅰ比值增高（P<0.05，图5B），这表明经过125I粒籽辐照后的过表达AKT1的肝癌细胞可部分恢复其自噬水平。经过以上实验证明过表达肝癌细胞中AKT1后抑制了125I粒籽辐照引起的肝癌细胞自噬。
2.6　过表达AKT1后降低了肝癌细胞对125I粒籽辐照敏感性
为了进一步探究AKT1对125I粒籽辐照后的肝癌细胞的影响，利用过表达AKT1的HUH7和Hep3B细胞进行了细胞存活能力和克隆能力的检测。对过表达AKT1的肝癌细胞进行125I粒籽辐照，流式细胞检测发现，在HUH7和Hep3B肝癌细胞中AKT1组与NC组凋亡率未见显著差异（P>0.05），AKT1+125I组较125I组凋亡率降低（P<0.05），AKT1+125I组较AKT1组凋亡率升高（P<0.05），这表明过表达AKT1的肝癌细胞在未接受125I粒籽辐照时，其存活能力与野生型未见明显差异（P>0.05），但在接受125I粒籽辐照后，过表达AKT1的肝癌细胞仍在辐照下发生凋亡，但是其生存率较125I组提高（P<0.05，图6A）。通过平板克隆实验检测过表达AKT1肝癌细胞的克隆能力，发现HUH7和Hep3B细胞系存在差异，在HUH7中AKT1组较NC组肝癌细胞克隆集落数未见明显差异（P>0.05），但是AKT1+125I组较125I组肝癌细胞克隆能力提高（P<0.05）；在Hep3B细胞中，AKT1组较NC组肝癌细胞克隆能力增高（P<0.05），AKT1+125I组较125I组肝癌细胞克隆能力提高（P<0.05，图6B）。综上结果表明，过表达AKT1会抑制肝癌细胞对125I粒籽辐照敏感性。
3　讨论
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3.1　 125I粒籽辐照肝癌细胞特性及临床应用优势
在本研究中，125I粒籽辐照后的肝癌细胞凋亡率升高，细胞克隆能力下降，这意味着125I粒籽辐照后的肝癌细胞生存能力下降。125I放射性粒籽植入是当前广泛应用于恶性肿瘤局部放疗的一种手段，具有安全性和有效性。125I放射性粒籽在实体性肿瘤中可持续释放射线，以粒籽为中心在近距离范围内进行低剂量率的持续放射治疗。由于其辐射剂量会随着距离的增加而减少，所以在实体肿瘤中植入125I粒籽可以提高肿瘤局部放射剂量的同时对周围组织的损伤也相应减少［11］。例如，在一项肝动脉化疗栓塞联合125I粒籽植入治疗原发性肝癌的系统评价和Meta分析研究中，473例患者接受经导管动脉化疗栓塞术（transcatheter arterial chemoembolization，TACE）联合125I粒籽植入治疗，另有421例患者仅接受TACE治疗，结果显示，接受联合治疗的患者1年和2年生存率均高于仅接受TACE治疗的患者［12-13］。这些研究表明125I粒籽在治疗肝癌中达到了良好的效果，有广阔的应用前景。
3.2　 125I粒籽在肝癌细胞中通过自噬促进细胞凋亡
在本研究中，125I粒籽辐照后的肝癌细胞中p62表达降低，LC3Ⅱ/LC3Ⅰ比值增高，这意味着在125I粒籽辐照后有自噬现象的发生。通过使用自噬的抑制剂氯喹和诱导剂雷帕霉素来验证125I放射性粒籽辐照肝癌细胞产生的自噬现象在癌症治疗中的作用。在癌症的发展过程中，自噬通常被认为是一把“双刃剑”，可以促进肿瘤的发生和抑制肿瘤的进展，这种自相矛盾的功能取决于癌症发展的不同阶段［14］，SUN等［15］研究发现外泌体miR-101-3 p抑制电离辐射引起的DNA损伤修复，通过激活PI3K/AKT/mTOR信号通路促进细胞和动物水平的自噬，从而引起非小细胞肺癌的凋亡。WANG等［16］的研究也发现电离辐射通过mTOR通路诱导自噬从而促进了卵巢癌细胞等的凋亡。结果表明125I放射性粒籽在肝癌中发挥作用是通过了诱发肝癌细胞的致命性自噬，从而促进肝癌细胞的凋亡。
3.3　AKT1介导肝癌细胞对125I粒籽的放疗敏感性
在本研究中通过125I粒籽辐照后的肝癌蛋白组数据库，筛选出核心表达差异蛋白AKT1，并对其在125I粒籽辐照后的肝癌细胞中所发挥的作用进一步探究。AKT1蛋白的过度活化和PI3 K/AKT信号通路的改变促进肿瘤进展，并促进不同癌症的化疗药物耐药性［17］。研究证明通过抑制AKT1可以抑制乳腺癌［18］、胃癌［19］等癌症的进展。因此，AKT1被认为是癌症的治疗靶点，有大量的研究对癌症靶点进行化学药物预防研究，其中也包括对AKT1抑制剂的研究，目前许多化合物已被认定为AKT1的抑制剂，其中包括卡匹塞替尼（capivasertib，AZD5363）、依帕塞替尼（ipatasertib，GDC-0068）和阿呋塞替尼（afuresertib，LAE002）等［20-21］。YU等［22］发现AKT1抑制剂可以诱导肝癌细胞的自噬性死亡。同时SHI等［23］发现AKT1可以作为自噬抑制剂介导卵巢癌细胞的对顺铂的耐药性。本研究发现在肝癌细胞中125I粒籽可以作为AKT1的抑制剂，125I粒籽辐照后的肝癌细胞中AKT1表达降低，从而促进肝癌细胞的自噬发生，紧接着构建了AKT1过表达的HUH7和Hep3B细胞系进行进一步的探究，结果表明AKT1过表达后，自噬现象受到了明显抑制。相较于仅过表达AKT1的肝癌细胞，过表达AKT1且经125I粒籽辐照处理的肝癌细胞自噬水平显著提升，这一现象表明，可能有其他分子参与125I粒籽辐照后肝癌细胞自噬的发生。
本研究存在一定的局限性。该研究仅通过体外细胞实验探究125I粒籽辐照后的肝癌细胞中AKT1与自噬的关系，但对其中具体的信号转导通路并未进一步明晰。
综上所述，125I粒籽辐照后的肝癌细胞的生存能力和克隆能力均下降。同时125I粒籽辐照后的肝癌细胞中AKT1的表达下降，这诱导了致命性自噬的发生。本研究结果表明125I粒籽可以作为一种AKT1的抑制剂从而诱导肝癌细胞自噬的发生，增加肝癌细胞的凋亡率，这为125I放射性粒籽植入治疗肝癌提供了新的解释。

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2025年第47卷第6期
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doi: 10.16016/j.2097-0927.202411028
  • 接收时间：2024-11-06
  • 首发时间：2026-10-30
  • 出版时间：2025-03-30
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  • 收稿日期：2024-11-06
  • 修回日期：2024-11-22
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    1陆军军医大学（第三军医大学）第一附属医院核医学科，重庆

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黄学全，E-mail：
HUANG Xuequan，E-mail：
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2种不同金属材料的力学参数
科
Family		 属数
Number of
genus		 种数
Number of
species		 占总种数比例
Percentage of
total species (%)		 属
Genus		 种数
Number of
species		 占总种数比例
Percentage of total
species (%)
鹅膏菌科Amanitaceae 2 11 5.26 鹅膏菌属 Amanita 10 4.78
小菇科 Mycenaceae 2 12 5.74 丝盖伞属 Inocybe 5 2.39
多孔菌科 Polyporaceae 8 14 6.70 蜡蘑属 Laccaria 5 2.39
红菇科 Russulaceae 3 23 11.00 小皮伞属 Marasmius 6 2.87
小菇属 Mycena 11 5.26
光柄菇属 Pluteus 5 2.39
红菇属 Russula 17 8.13
栓菌属 Trametes 5 2.39
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